US11873346B2ActiveUtilityA1

VISTA antigen-binding molecules

58
Assignee: HUMMINGBIRD BIOSCIENCE PTE LTDPriority: Sep 7, 2018Filed: Mar 18, 2020Granted: Jan 16, 2024
Est. expirySep 7, 2038(~12.2 yrs left)· nominal 20-yr term from priority
Inventors:Jerome Douglas Boyd-KirkupPiers IngramDipti ThakkarZhihao WuKonrad PaszkiewiczVicente SancenonSiyu Guan
C07K 16/464C07K 16/468C07K 2317/522C07K 2317/524C07K 2317/526C07K 2317/565C07K 2317/567C07K 2317/72C07K 16/2827C07K 2317/92C07K 2317/33C07K 2317/76C07K 2317/94A61K 2039/505A61P 35/00A61K 2039/507C07K 2317/52C07K 2317/71
58
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Cited by
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References
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Claims

Abstract

VISTA antigen-binding molecules are disclosed. Also disclosed are nucleic acids and expression vectors encoding, compositions comprising, and methods using, the VISTA antigen-binding molecules.

Claims

exact text as granted — not AI-modified
The invention claimed is: 
     
       1. An antigen-binding molecule comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the antigen-binding molecule binds specifically to and displays cross-reactivity with both to human VISTA and mouse VISTA, wherein the antigen-binding molecule inhibits VISTA-mediated signalling independently of Fc-mediated function, and wherein the antigen-binding molecule comprises:
 a VH region incorporating the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:305 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:306 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:307; and 
 
 a VL region incorporating the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:308 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43. 
 
 
     
     
       2. The antigen-binding molecule according to  claim 1 , wherein the antigen-binding molecule comprises:
 (a)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:309 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (b)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:295 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (c)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:300 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (d)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (e)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:277 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (f)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:286 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (g)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:244 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:245 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (h)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:53 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:58 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (i)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:67 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (j)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43. 
 
 
 
     
     
       3. The antigen-binding molecule according to  claim 1 , wherein the antigen-binding molecule comprises:
 (a) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:310; or 
 (b) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:297; or 
 (c) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:294; or 
 (d) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:299; or 
 (e) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:301; or 
 (f) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:302; or 
 (g) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:285; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:287; or 
 (h) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:52; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:57; or 
 (i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:62; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:66; or 
 (j) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:32; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:40. 
 
     
     
       4. A nucleic acid, or a plurality of nucleic acids, encoding an antigen-binding molecule comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the antigen-binding molecule binds specifically to and displays cross-reactivity with both human VISTA and mouse VISTA, wherein the antigen-binding molecule inhibits VISTA-mediated signalling independently of Fc-mediated function, and wherein the antigen-binding molecule comprises:
 a VH region incorporating the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:305 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:306 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:307; and 
 
 a VL region incorporating the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:308 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43. 
 
 
     
     
       5. The nucleic acid or plurality of nucleic acids according to  claim 4 , wherein the antigen-binding molecule comprises:
 (a)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:309 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (b)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:295 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (c)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:300 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (d)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (e)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:277 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (f)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:286 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (g)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:244 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:245 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (h)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:53 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:58 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (i)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:67 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (j)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43. 
 
 
 
     
     
       6. The nucleic acid or plurality of nucleic acids according to  claim 4 , wherein the antigen-binding molecule comprises:
 (a) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:310; or 
 (b) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:297; or 
 (c) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:294; or 
 (d) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:299; or 
 (e) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:301; or 
 (f) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:302; or 
 (g) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:285; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:287; or 
 (h) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:52; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:57; or 
 (i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:62; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:66; or 
 (j) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:32; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:40. 
 
     
     
       7. A cell comprising a nucleic acid, or a plurality of nucleic acids, encoding an antigen-binding molecule comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the antigen-binding molecule binds specifically to and displays cross-reactivity with both human VISTA and mouse VISTA, wherein the antigen-binding molecule inhibits VISTA-mediated signalling independently of Fc-mediated function, and wherein the antigen-binding molecule comprises:
 a VH region incorporating the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:305 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:306 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:307; and 
 
 a VL region incorporating the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:308 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43. 
 
 
     
     
       8. The cell according to  claim 7 , wherein the antigen-binding molecule comprises:
 (a)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:309 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (b)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:295 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (c)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:300 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (d)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (e)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:277 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (f)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:286 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (g)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:244 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:245 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (h)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:53 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:58 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (i)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs: 
 
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 LC-CDR2 having the amino acid sequence of SEQ ID NO:67 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 (j)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43. 
 
 
 
     
     
       9. The cell according to  claim 7 , wherein the antigen-binding molecule comprises:
 (a) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:310; or 
 (b) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:297; or 
 (c) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:294; or 
 (d) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:299; or 
 (e) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:301; or 
 (f) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:302; or 
 (g) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:285; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:287; or 
 (h) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:52; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:57; or 
 (i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:62; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:66; or 
 (j) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:32; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:40. 
 
     
     
       10. A method of treating a cancer in a subject, comprising administering to a subject a therapeutically effective amount of an antigen-binding molecule comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the antigen-binding molecule binds specifically to and displays cross-reactivity with both human VISTA and mouse VISTA, wherein the antigen-binding molecule inhibits VISTA-mediated signalling independently of Fc-mediated function, and wherein the antigen-binding molecule comprises:
 a VH region incorporating the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:305 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:306 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:307; and 
 
 a VL region incorporating the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:308 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43. 
 
 
     
     
       11. The method according to  claim 10 , wherein the antigen-binding molecule comprises:
 (a) 
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:309 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (b)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:295 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (c)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:300 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (d)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:290 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:291 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (e)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:277 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (f)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:286 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (g)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:244 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:245 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (h)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:53 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:58 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (i)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:67 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43; or 
 
 
 (j)
 a VH region having the following CDRs:
 HC-CDR1 having the amino acid sequence of SEQ ID NO:33 
 HC-CDR2 having the amino acid sequence of SEQ ID NO:34 
 HC-CDR3 having the amino acid sequence of SEQ ID NO:35; and 
 
 a VL region having the following CDRs:
 LC-CDR1 having the amino acid sequence of SEQ ID NO:41 
 LC-CDR2 having the amino acid sequence of SEQ ID NO:42 
 LC-CDR3 having the amino acid sequence of SEQ ID NO:43. 
 
 
 
     
     
       12. The method according to  claim 10 , wherein the antigen-binding molecule comprises:
 (a) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:310; or 
 (b) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:297; or 
 (c) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:294; or 
 (d) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:299; or 
 (e) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:301; or 
 (f) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:302; or 
 (g) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:285; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:287; or 
 (h) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:52; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:57; or 
 (i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:62; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:66; or 
 (j) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:32; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:40. 
 
     
     
       13. The method according to  claim 10 , wherein the cancer is selected from the group consisting of: a cancer comprising cells expressing VISTA, a cancer comprising infiltration of cells expressing VISTA, a cancer comprising cancer cells expressing VISTA, a hematological cancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, T cell lymphoma, multiple myeloma, mesothelioma, a solid tumor, lung cancer, non-small cell lung carcinoma, gastric cancer, gastric carcinoma, colorectal cancer, colorectal carcinoma, colorectal adenocarcinoma, uterine cancer, uterine corpus endometrial carcinoma, breast cancer, triple negative breast invasive carcinoma, liver cancer, hepatocellular carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, thyroid cancer, thymoma, skin cancer, melanoma, cutaneous melanoma, kidney cancer, renal cell carcinoma, renal papillary cell carcinoma, head and neck cancer, squamous cell carcinoma of the head and neck (SCCHN), ovarian cancer, ovarian carcinoma, ovarian serous cystadenocarcinoma, prostate cancer and prostate adenocarcinoma.

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